A human body has approximately 20 billion or more adipocytes, and if supplies of energy are extremely excessive to demands thereon, triglycerides are stored in the adipocytes in the human body, which are degraded into free fatty acids and glucose, which will be used as an energy source upon the exhaustion of energy.
Obesity, which about 30 to about 40% of people of today have, occurs when excessive energy is accumulated due to imbalance of the above process, and shows the increased size and number of adipocytes. The hygienic environment has been improved due to improvement in the standard of living resulting from the recent economic development, frequent consumption of instant food products and changes in dietary habits toward the consumption of more meat induce the accumulation of excessive amounts of caloric energy in the body. These changes in dietary habits of people of today show a tendency of a rapid increase in the obese population in addition to a decrease in consumption of calories due to the lack of exercise. This obesity is so closely associated with a metabolic syndrome that obesity may be used for the diagnosis of a metabolic syndrome.
The metabolic syndrome is a term used to conceptualize a cluster of risk factors of various cardiovascular diseases and type 2 diabetes mellitus as one disease group. This is a useful concept which may comprehensively explain all of the insulin resistance and complex and various metabolic disorders and clinical aspects associated with the same, and refers to a syndrome in which risk factors such as obesity, diabetes, fatty liver and hypertriglyceridemia are together increased. Accordingly, when a person gets a metabolic syndrome, the risk of developing a cardiovascular disease or type 2 diabetes mellitus is increased. According to the ATPIII of US National Cholesterol Education Program published in 2001, when a patient develops three or more of five risk factors such as an abdomen-obesity of 40 inch (102 cm) for a man and 35 inch (88 cm) for a woman in terms of waist circumference, a triglyceride level of 150 mg/dL or more, a HDL cholesterol level of 40 mg/dL or less for a man and 50 mg/dL or less for a woman, a blood pressure of 130/85 mmHg or more, and a fasting glucose of 110 mg/dL or more, the patient is diagnosed with a metabolic syndrome.
Insulin resistance refers to a phenomenon in which even though insulin is normally secreted in vivo, insulin does not induce sufficient supply of glucose to cells. Therefore, glucose in the blood cannot enter cells, thus causing hyperglycemia, and thereby cells cannot perform normal functions due to a shortage of glucose, leading to the manifestation of a metabolic syndrome. The diabetic symptoms thus developed are classified into type 2 diabetes mellitus (T2DM, noninsulin-dependent diabetes mellitus: NIDDM), which is different from type 1 diabetes mellitus (insulin-dependent diabetes mellitus). For this reason, the most preferred method of treating type 2 diabetes mellitus is to induce insulin so as to perform normal functions by improving insulin resistance. Nevertheless, an agent for improving insulin resistance has been scarcely developed so far. Most of the agents for treating type 2 diabetes mellitus currently in use or developed are targeted to further increase the amount of insulin secreted in order to compensate for the lost function of insulin caused by insulin resistance. However, when the amount of insulin secreted in our body is increased, obesity and inflammation are definitely caused, thereby resulting in various side effects such as an increase in cancer incidence, so that unless the problem of insulin resistance is fundamentally alleviated, a temporary normalization of blood sugar may be expected, but a result that health gradually deteriorates is only obtained. For this reason, there is more urgent need in society for a therapeutic agent for type 2 diabetes mellitus, which may normalize blood sugar by alleviating insulin resistance.
Meanwhile, Patent Document 1 discloses the use of glabridin for preventing or treating a metabolic syndrome including hyperlipidemia, fatty liver, glucose metabolism disorder, diabetes and obesity:
Glabridin is known to be effective not only for a metabolic syndrome including hyperlipidemia, fatty liver, glucose metabolism disorder, diabetes and obesity, but also for prevention and treatment such as anti-inflammatory action and anticancer action, but is easily broken down by sunlight, moisture, acidity, basicity, oxygen, heat and the like due to low chemical stability, so that it is very difficult to develop a product utilizing glabridin (Non-Patent Document 1).
According to various studies hitherto published, leptin resistance and insulin resistance are each considered to be an important cause for obesity and type 2 diabetes mellitus (T2DM), and the most representative and inventive mechanism causing these resistances is due to a problem caused during the signaling process in a leptin receptor and an insulin receptor (IR), and both the receptors are commonly closely associated with protein tyrosine phosphatase 1B (PTP1B) (Non-Patent Document 2).
Only from the fact that the signaling process of both leptin (a signaling material which promotes food intake and energy consumption) and insulin (a signaling material which promotes carbohydrate uptake and lipid synthesis) which are the most important hormones associated with the accumulation of energy in our body, it is enough for PTP1B to draw people's attention as the most important therapeutic target for obesity and diabetes. In addition, since the year 2000 in which the action mechanism on PTP1B was clearly identified, PTP1B has actually drawn most attention as an important pharmacological mechanism for treating obesity, type 2 diabetes mellitus, and cancer. That is, a PTP1B inhibitor, which may arbitrarily control the activity of PTP1B, is highly likely to be developed as a therapeutic agent for obesity and type 2 diabetes mellitus, which normalizes the activity of leptin and insulin by alleviating leptin and insulin resistance (Non-Patent Documents 3 and 4).
According to research results revealed by various studies recently conducted, it has been found that PTP1B is closely associated with not only obesity and diabetes, but also various inflammatory diseases, heart diseases, endoplasmic reticulum stress diseases, breast cancer, prostate cancer and the like. As described above, while it has been found that various chronic diseases referred to as adult diseases in a typical sense are directly and indirectly associated with PTP1B, PTP1B has been highlighted as an important and fundamental therapeutic target for treating these adult diseases. In this sense, it is not too much to say that PTP1B is the most basic and fundamental cause of disease, which forms the bottom of many adult diseases (Non-Patent Document 5).